This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding immune responses is critical to making progress in areas such as AIDS research. The yellow fever vaccine-17D (YFV-17D) is one of the most successful vaccines ever developed, yet we understand little of the mechanisms by which it induces protective immunity. Research during the previous cycle has focused on understanding the immunological mechanisms by which YFV-17D stimulates broad and long lasting T and B cell responses. The results of this work can be summed up thus: (i) YFV-17D stimulates multiple Toll-like receptors (TLRs) on dendritic cells (DCs), and this leads to robust CD8+ T cell responses and a mixed Th1/Th2 profile. Furthermore, YFV-17D induces the mammalian target of ramayicn (mTOR) in plasmacytoid DCs, which mediates type I IFN production, and enhances the CD8+ T cell response. (ii) A systems biological analysis of humans vaccinated with YFV-17D, demonstrated a robust type I IFN genomic signature in most vaccines. Importantly, a distinct signature which included eukaryotic translation initiation factor 2 alpha kinase 4 [EIF2AK4, a stress response gene, was capable of predicting with 90% accuracy the magnitude of the CD8+ T cell responses. (iii) Analysis of an individual who developed serious adverse events shortly after YFV-17D vaccination, revealed robust T and B cell responses, but polymorphisms in the CCR5 and RANTES genes, and greatly enhanced numbers of inflammatory monocytes. Taken together, these observations provide new insights into the mode of action of YFV-17D.